The neuropeptide cholecystokinin-8 (CCK-8) is an important neuromodulator and neurotransmitter in the brain. There are two types of CCK receptor which are currently referred to as CCK.sub.A and CCK.sub.B receptors. The major of the CCK receptor types in brain is the CCK.sub.B receptor (Review by Woodruff & Hughes, Annual Review of Pharmacology Toxicology 31:469-501 (1991)).
The functional role of CCK in brain is not fully understood. Recently there has been evidence that CCK is involved in anxiety and that CCK.sub.B antagonists have an anxiolytic action in animal models of anxiety (Hughes, et al, Proc Natnl Acad Sci, USA 87:6728-6732 (1990).
It has recently been shown (de Montigny, C Arch Gen Psychiatry 46:511-517 (1989) ; Bradwejn J, Koszyckl, D, and Metesissian, G, Can J Psychiatr 35:83-85 (1990) that the injection of the tetrapeptide cholecystokinin (30-33) (CCK-4) into human volunteers or into patients suffering from panic disorder precipitates a panic attack. The tetrapeptide cholecystokinin (30-33) (CCK-4) is a substance that stimulates CCK.sub.B receptors, i.e., is a CCK.sub.B antagonist. The injection of the tetrapeptide cholecystokinin (30-33) (CCK-4) into the cerebral ventricles of the brain of rats precipitates the onset of an anxiogenic reaction. This anxiogenic response can be prevented by pretreatment of the rats with the CCK.sub.B antagonist CI-988 (Sing, et al, Proc Natnl Acad Sci USA 88:1130-1133 (1991)).
The present invention relates to compounds known as dipeptoids and/or their pharmaceutically acceptable salts for use in the prevention of panic attacks in patients prone to these attacks. Suitable compounds are cholecystokinin (CCK).sub.B antagonists such as [R-(R*,R*)]-4-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo [3.3.1.1.sup.3,7]dec-2-yloxy)carbonyl[amino[propyl[amino]-1-phenylethyl]am ino]-4-oxobutanoic acid (CI-988).
The compounds useful in this invention are fully described in U.S. Ser. No. 07/629,809, filed Dec. 19, 1990. Methods of preparing the compounds, intermediates useful in their preparation, compositions containing the compounds, and uses of the compounds are disclosed. The uses disclosed include the treatment of obesity, hypersecretion of gastric acid in the gut, gastrin-dependent tumors, psychoses, anxiety, ulcer, depression, withdrawal response produced by chronic treatment or use followed by withdrawal from nicotine, diazepam, alcohol, cocaine, caffeine, or opioids.
The disclosure of U.S. Ser. No. 07/629,809 is incorporated herein by reference.